tbuckley/cabot-search huggingface dataset:
PB2011: TRANSFUSION BURDEN IS AN IMPORTANT PROGNOSTIC FACTOR IN LOWER-RISK MYELODYSPLASTIC SYNDROME
Authors: Jungmin Lee, Juhyung Kim, Hee Jeong Cho, Dong Won Baek, Ji Yeon Ham, Soon Hee Chang, Sang Kyun Sohn, Young Rok Do, Joon Ho Moon
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: The transfusion burden differs among patients with lower-risk myelodysplastic syndrome (LR-MDS), and those receiving red blood cell (RBC) transfusions are at risk of iron overload. In such cases, the binding capacity of transferrin for iron is surpassed, resulting in non–transferrin-bound iron circulating in the blood and subsequent deposition of free iron in tissues, which can cause significant organ damage and is an important cause of morbidity and mortality. Although new agent such as luspatercept showed a notable response in transfusion-dependent patients with LR-MDS, many patients still need RBC transfusions. Therefore, determining the clinical outcomes of transfusion burden and optimizing treatment for patients with MDS with transfusion dependencies are important. Recently, the MDS International Working Group (IWG) has established criteria for transfusion dependence and defined three categories: non-transfusion-dependent (NTD), low transfusion burden (LTB), and high transfusion burden (HTB). Aims: This study retrospectively analyzed the prognostic impact of transfusion burden in patients with LR-MDS and the outcomes of each treatment option. Methods: Data on 168 patients with LR-MDS between July 2011 and April 2020 were retrospectively reviewed. Non-transfusion-dependent (NTD) was defined as no transfusion history in a period of 16 weeks, low transfusion burden (LTB) as receiving 3–7 red blood cell (RBC) units in a period of 16 weeks, and high transfusion burden (HTB) as receiving ≥8 RBC units in a period of 16 weeks. The treatment response was observed over 4–6 months after treatment. Results: Among the 168 patients, 105 were treated with anabolic steroids (n = 65), erythroid stimulating agents (n = 12), or hypomethylating agents (n = 28). The overall response rate was 53.3% (56/105), with 53 patients showing hematologic improvement (50.5%). The clinical benefit rate was 78.1% (82/105). The 5-year overall survival (OS) rates were 75.5%, 45.8%, and 33.3% for NTD, LTB, and HTB, respectively (p = 0.001). The 5-year incidence of acute myeloid leukemia were 0%, 9.9%, and 32.5% in NTD, LTB, and HTB, respectively (p < 0.001). In the multivariate analysis, age (hazard ratio [HR] 1.04, p = 0 009), LTB (HR 3.77, p = 0.002), HTB (HR 4.59, p < 0.001), and hemoglobin response (HR 0.45, p = 0.036) were significant factors for OS. Summary/Conclusion: Our findings show that transfusion dependency is an adverse prognostic factor in LR-MDS. Furthermore, HTB presented a higher risk of leukemic transformation.Keywords: Myelodysplastic syndrome, Transfusion, Prognostic factor
MY‐1‐Loaded Nano‐Hydroxyapatite Accelerated Bone Regeneration by Increasing Type III Collagen Deposition in Early‐Stage ECM via a Hsp47‐Dependent Mechanism (Adv. Healthcare Mater. 20/2023)
Authors: Zhang Yanli, Mo Jiayao, Zheng Chunqing, Zeng Yuting, Zhou Zhiyan, Zhang Yulin, Li Minghan, Shao Longquan, Yang Dehong, Yan Wenjuan
Journal: Advanced Healthcare Materials (2023)

Osteogenesis In article 2300332 by Shao Longquan, Yang Dehong, Yan Wenjuan and co-workers, the peptide MY-1-loaded nHA can extend the MY-1 releasing period in a local bone defect. Then, MY-1 is endocytosed by parathyroid hormone 1 receptor (PTH1R) and induces the upregulation and nuclear translocation of β-catenin, thereby promoting the expression of Hsp47 and accelerating the synthesis and secretion of collagen at early stage, thus promoting the early osteogenesis and bone regeneration.
Mesenchymal Stem Cell Aggregation‐Released Extracellular Vesicles Induce CD31<sup>+</sup>EMCN<sup>+</sup> Vessels in Skin Regeneration and Improve Diabetic Wound Healing (Adv. Healthcare Mater. 20/2023)
Authors: Lu Liu, Chen‐Xi Zheng, Na Zhao, Ting Zhu, Cheng‐Biao Hu, Nan Zhang, Ji Chen, Kai‐Chao Zhang, Sha Zhang, Jie‐Xi Liu, Kai Zhang, Huan Jing, Bing‐Dong Sui, Yan Jin, Fang Jin
Journal: Advanced Healthcare Materials (2023)

Extracellular Vesicles In article number 2300019, Bing-Dong Sui, Yan Jin, Fang Jin, and co-workers discover mesenchymal stem cell aggregates secrete angiogenic extracellular vesicles, which exert high efficacy in boosting CD31+EMCN+ vessels with adjacent cell proliferation and provide an effective therapy to alleviate non-healing diabetic wounds.
Multicenter Phase II Trial of Lenvatinib plus Hepatic Intra-Arterial Infusion Chemotherapy with Cisplatin for Advanced Hepatocellular Carcinoma: LEOPARD
Authors: Masafumi Ikeda, Tatsuya Yamashita, Sadahisa Ogasawara, Masatoshi Kudo, Yoshitaka Inaba, Manabu Morimoto, Kaoru Tsuchiya, Satoshi Shimizu, Yasushi Kojima, Atsushi Hiraoka, Kazuhiro Nouso, Hiroshi Aikata, Kazushi Numata, Tosiya Sato, Takuji Okusaka, Junji Furuse
Journal: Liver Cancer (2023)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Hepatic arterial infusion chemotherapy (HAIC) with cisplatin and lenvatinib exhibits strong antitumor effects against advanced hepatocellular carcinoma (HCC). Higher antitumor activity is expected for the combination treatment. The aim of this trial was to evaluate the efficacy and safety of lenvatinib in combination with HAIC using cisplatin in patients with advanced HCC. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; In this multicenter, open-labeled, single-arm, phase II trial, patients with advanced HCC categorized as Child-Pugh class A with no prior history of systemic therapy were enrolled. Patients received lenvatinib plus HAIC with cisplatin (lenvatinib: 12 mg once daily for patients ≥60 kg, 8 mg once daily for patients &amp;lt;60 kg; HAIC with cisplatin: 65 mg/m&lt;sup&gt;2&lt;/sup&gt;, day 1, every 4–6 weeks, maximum of six cycles). The primary endpoint was the objective response rate (ORR) assessed using modified RECIST by the Independent Review Committee. The secondary endpoints were the ORR assessed using RECIST v1.1, progression-free survival, overall survival, and frequency of adverse events associated with the treatment. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A total of 36 patients were enrolled between September 2018 and March 2020. In the 34 evaluable patients, the ORR assessed by the Independent Review Committee using modified RECIST and RECIST v1.1 were 64.7% (95% confidence interval [CI]: 46.5–80.3%) and 45.7% (95% CI: 28.8–63.4%), respectively. The median progression-free survival and overall survival were 6.3 months (95% CI: 5.1–7.9 months) and 17.2 months (95% CI: 10.9 – not available, months), respectively. The main grade 3–4 adverse events were increased aspartate aminotransferase (34%), leukopenia (22%), increased alanine aminotransferase (19%), and hypertension (11%). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Lenvatinib plus HAIC with cisplatin yielded a favorable ORR and overall survival and was well tolerated in patients with advanced HCC. Further evaluation of this regimen in a phase III trial is warranted.
FXR agonists in NASH treatment
Authors: Luciano Adorini, Michael Trauner
Journal: Journal of Hepatology (2023)

The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor highly expressed in the liver and intestine, regulates the expression of genes involved in cholesterol and bile acid homeostasis, hepatic gluconeogenesis, lipogenesis, inflammation and fibrosis, in addition to controlling intestinal barrier integrity, preventing bacterial translocation and maintaining gut microbiota eubiosis. Non-alcoholic steatohepatitis (NASH), an advanced stage of non-alcoholic fatty liver disease, is characterized by hepatic steatosis, hepatocyte damage (ballooning) and inflammation, leading to fibrosis, cirrhosis and hepatocellular carcinoma. NASH represents a major unmet medical need, but no pharmacological treatments have yet been approved. The pleiotropic mechanisms involved in NASH development offer a range of therapeutic opportunities and among them FXR activation has emerged as an established pharmacological target. Various FXR agonists with different physicochemical properties, which can be broadly classified as BA derivatives, non-BA-derived steroidal FXR agonists, non-steroidal FXR agonists, and partial FXR agonists, are in advanced clinical development. In this review we will summarize key preclinical and clinical features of the most advanced FXR agonists and critically evaluate their potential in NASH treatment.
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
Authors: Philip N. Newsome, Phil Ambery
Journal: Journal of Hepatology (2023)

The principle pathological drivers of metabolic dysfunction associated steatohepatitis (MASH) are obesity and associated insulin resistance, rendering them key therapeutic targets. As Glucagon-like Peptide 1 receptor agonists (GLP-1RA) have been licensed for the treatment of diabetes and obesity they were one of the first such drugs to be evaluated in patients with MASH. Successful phase 2a and 2b studies have resulted in progression to Phase 3 clinical trials. Alongside GLP-1RA, newer combinations with Glucagon agonism and/or with Glucose-dependent Insulinotropic Peptide (GIP) agonism have been explored in related patient groups with evidence of improvements in weight loss, insulin resistance and non-invasive liver parameters. There remains debate as to whether GLP-1 receptor agonists have direct, independent effects to improve MASH or whether they impact on pathophysiology through improvements in weight, insulin resistance and glycaemic control. Combinations are being explored although this needs to be weighed against the cumulative side-effect burden, potential drug-drug interactions and cost of goods. There is also uncertainty regarding the optimal ratio of glucagon and GIP agonism to GLP-1 agonism in combination agents, and as to whether GIP agonism or antagonism is indeed the optimal approach. Finally, there are also multiple hypothetical permutations combining gut hormone agonists with the emerging assets in the field. Given that the likely dominant mode of action of gut hormone agonists is upstream on weight initial combinations might focus on agents which have been shown to have a more direct effect on fibrosis which would include FGF21 and pan-PPAR agonists
Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders
Authors: Eric J. Nunes, Nii A. Addy, P. Jeffrey Conn, Daniel J. Foster
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.
MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with <i>MTAP</i>-Deleted Cancer
Authors: Lars D. Engstrom, Ruth Aranda, Laura Waters, Krystal Moya, Vickie Bowcut, Laura Vegar, David Trinh, Allan Hebbert, Christopher R. Smith, Svitlana Kulyk, J. David Lawson, Leo He, Laura D. Hover, Julio Fernandez-Banet, Jill Hallin, Darin Vanderpool, David M. Briere, Alice Blaj, Matthew A. Marx, Jordi Rodon, Michael Offin, Kathryn C. Arbour, Melissa L. Johnson, David J. Kwiatkowski, Pasi A. Jänne, Candace L. Haddox, Kyriakos P. Papadopoulos, Jason T. Henry, Konstantinos Leventakos, James G. Christensen, Ronald Shazer, Peter Olson
Journal: Cancer Discovery (2023)

Abstract Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with &amp;gt;70-fold selecti­vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non–small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. Significance: PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293
Inferring the Direction of Introgression Using Genomic Sequence Data
Authors: Yuttapong Thawornwattana, Jun Huang, Tomáš Flouri, James Mallet, Ziheng Yang
Journal: Molecular Biology and Evolution (2023)

Abstract Genomic data are informative about the history of species divergence and interspecific gene flow, including the direction, timing, and strength of gene flow. However, gene flow in opposite directions generates similar patterns in multilocus sequence data, such as reduced sequence divergence between the hybridizing species. As a result, inference of the direction of gene flow is challenging. Here, we investigate the information about the direction of gene flow present in genomic sequence data using likelihood-based methods under the multispecies-coalescent-with-introgression model. We analyze the case of two species, and use simulation to examine cases with three or four species. We find that it is easier to infer gene flow from a small population to a large one than in the opposite direction, and easier to infer inflow (gene flow from outgroup species to an ingroup species) than outflow (gene flow from an ingroup species to an outgroup species). It is also easier to infer gene flow if there is a longer time of separate evolution between the initial divergence and subsequent introgression. When introgression is assumed to occur in the wrong direction, the time of introgression tends to be correctly estimated and the Bayesian test of gene flow is often significant, while estimates of introgression probability can be even greater than the true probability. We analyze genomic sequences from Heliconius butterflies to demonstrate that typical genomic datasets are informative about the direction of interspecific gene flow, as well as its timing and strength.
Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial
Authors: Moti N Ramgopal, Antonella Castagna, Charles Cazanave, Vicens Diaz-Brito, Robin Dretler, Shinichi Oka, Olayemi Osiyemi, Sharon Walmsley, James Sims, Giovanni Di Perri, Kenneth Sutton, Denise Sutherland-Phillips, Alessandro Berni, Christine L Latham, Feifan Zhang, Ronald D'Amico, Miguel Pascual Bernáldez, Rodica Van Solingen-Ristea, Veerle Van Eygen, Parul Patel, Vasiliki Chounta, William R Spreen, Harmony P Garges, Kimberly Smith, Jean van Wyk
Journal: The Lancet HIV (2023)
Nutritional supplementation to prevent tuberculosis incidence in household contacts of patients with pulmonary tuberculosis in India (RATIONS): a field-based, open-label, cluster-randomised, controlled trial
Authors: Anurag Bhargava, Madhavi Bhargava, Ajay Meher, Andrea Benedetti, Banurekha Velayutham, G Sai Teja, Basilea Watson, Ganesh Barik, Rajeev Ranjan Pathak, Ranjit Prasad, Rakesh Dayal, Adarsh Kibballi Madhukeshwar, Vineet Chadha, Madhukar Pai, Rajendra Joshi, Dick Menzies, Soumya Swaminathan
Journal: The Lancet (2023)
PB2397: TRANSCRIPTOME ANALYSIS OF DIFFUSE LARGE B-CELL LYMPHOMA CELLS EXPRESSING MYD88 L265P REVEALS CD44, LGALS3, NFKBIZ AND BATF AS DOWNSTREAM TARGETS OF ONCOGENIC NF-ΚB SIGNALING.
Authors: Marcello Turi, Anjana Anilkumar Sithara, Lucie Hofmanová, David Žihala, Dhwani Radhakrishnan, Alexander Vdovin, Sofija Knápková, Tereza Ševčíková, Zuzana Chyra, Tomas Jelínek, Michal Šimíček, Annamaria Gullà, Kenneth Anderson, Roman Hájek, Matous Hrdinka
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: Myeloid differentiation primary response 88 (MyD88) serves as a crucial signaling adaptor protein during innate immune responses, integrating stimuli from the Toll-like receptors (TLR) and Interleukin-1 receptor (IL-1R) family and translating them into specific cellular outcomes. In B cells, somatic mutations of MyD88 induce oncogenic NF-κB signaling independently of receptor stimulation, resulting in the onset of B-cell malignancies. However, the precise molecular mechanisms and downstream signaling targets remain unresolved. Aims: This study aims to investigate the impact of MyD88L265P oncogenic signaling on lymphoma cells by analyzing the transcriptomic response of model cell lines. Specifically, we aim to identify the downstream targets of MyD88L265P signaling that are either upregulated or downregulated and may play a role in cellular transformation. Methods: Our study utilized an inducible expression system to introduce MyD88 into lymphoma cell lines acutely. We performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed due to the MyD88 L265P oncogenic mutation. To validate the RNA-seq hits, we employed additional experimental techniques such as qPCR, flow cytometry, and immunoblotting. Furthermore, we conducted database searches to support our findings and strengthen the relevance of the identified targets in the context of cellular transformation. Results: We show that MyD88L265P activates the NF-κB signaling pathway and upregulates genes that might contribute to lymphomagenesis, including membrane receptors CD44 and LGALS3 (coding Galectin-3), and transcription factors NFKBIZ (coding IkBƺ) and BATF. Moreover, we demonstrate that CD44 can serve as a novel biomarker of the activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL). Finally, we show that CD44 expression negatively correlates with overall survival in DLBCL patients using publicly available datasets. Summary/Conclusion: Our results shed new light on downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation, thus providing novel biomarkers and potential therapeutical targets.Keywords: Signaling, CD44, Oncogene, DLBCL
Evaluating the safety and short-term equivalence of colchicine versus prednisone in older patients with acute calcium pyrophosphate crystal arthritis (COLCHICORT): an open-label, multicentre, randomised trial
Authors: Tristan Pascart, Pierre Robinet, Sébastien Ottaviani, Rémi Leroy, Nicolas Segaud, Aurore Pacaud, Agathe Grandjean, Hélène Luraschi, Thibault Rabin, Xavier Deplanque, Pierre Maciejasz, Fabien Visade, Alexandre Mackowiak, Nicolas Baclet, Sylvestre Maréchaux, Antoine Lefebvre, Jean-François Budzik, Thomas Bardin, Pascal Richette, Laurène Norberciak, Vincent Ducoulombier, Eric Houvenagel
Journal: The Lancet Rheumatology (2023)
Novel Antigens and Clinical Updates in Membranous Nephropathy
Authors: Rupali Avasare, Nicole Andeen, Laurence Beck
Journal: Annual Review of Medicine (2023)

Membranous nephropathy (MN), an autoimmune kidney disease and leading cause of nephrotic syndrome, leads to kidney failure in up to one-third of affected individuals. Most MN cases are due to an autoimmune reaction against the phospholipase A2 receptor (PLA2R) located on kidney podocytes. Serum PLA2R antibody quantification is now part of routine clinical practice because antibody titers correlate with disease activity and treatment response. Recent advances in target antigen detection have led to the discovery of more than 20 other podocyte antigens, yet the clinical impact of additional antigen detection remains unknown and is under active investigation. Here we review recent findings and hypothesize how current research will inform future care of patients with MN.
Genetic Incompatibilities and Evolutionary Rescue by Wild Relatives Shaped Grain Amaranth Domestication
Authors: José Gonçalves-Dias, Akanksha Singh, Corbinian Graf, Markus G Stetter
Journal: Molecular Biology and Evolution (2023)

Crop domestication and the subsequent expansion of crops have long been thought of as a linear process from a wild ancestor to a domesticate. However, evidence of gene flow from locally adapted wild relatives that provided adaptive alleles into crops has been identified in multiple species. Yet, little is known about the evolutionary consequences of gene flow during domestication and the interaction of gene flow and genetic load in crop populations. We study the pseudo-cereal grain amaranth that has been domesticated three times in different geographic regions of the Americas. We quantify the amount and distribution of gene flow and genetic load along the genome of the three grain amaranth species and their two wild relatives. Our results show ample gene flow between crop species and between crops and their wild relatives. Gene flow from wild relatives decreased genetic load in the three crop species. This suggests that wild relatives could provide evolutionary rescue by replacing deleterious alleles in crops. We assess experimental hybrids between the three crop species and found genetic incompatibilities between one Central American grain amaranth and the other two crop species. These incompatibilities might have created recent reproductive barriers and maintained species integrity today. Together, our results show that gene flow played an important role in the domestication and expansion of grain amaranth, despite genetic species barriers. The domestication of plants was likely not linear and created a genomic mosaic by multiple contributors with varying fitness effects for today's crops.